脑脊液中Dickkopf-1的表达与肺腺癌软脑膜转移发生发展及耐药性的相关性分析

Correlation analysis between the expression of Dickkopf-1 in the CSF and the oncogenesis,development and drug resistance of lung adenocarcinoma with leptomeningeal metastases

目的探讨LUAD伴LM患者CSF中的DKK1与LM发病、耐药性、预后的相关性。方法筛选就诊于南京鼓楼医院进行规律的培美曲塞鞘内化疗的LUAD伴LM患者20例,依据RANO疗效评价标准分为:疾病控制(disease control,DC)组,疾病进展(progressive disease,PD)组。收集入组患者及10例非瘤对照者脑脊液样本。其中DC组样本按治疗周期分为:DC-0C组(鞘内化疗前),DC-2C组(两周期鞘内化疗后),DC-4C组(四周期鞘内化疗后)。使用ELISA检测样本DKK1表达情况,分析其与患者临床特征、疗效、无进展生存期(progression-free survival,PFS)相关性。结果LUAD患者CSF中DKKl表达较非瘤对照升高(P<0.05),PD组上调更为显著(P<0.05)。DC组DKKl表达水平不断下降,DC-4C组较DC-0C组显著下降(P<0.05)。依据ROC曲线,CSF中DKK1最佳诊断截断点为139.36pg/mL(敏感性70%,特异性80%,AUC=0.745)。DC组与PD组患者PFS存在显著差异(P<0.01)。以截断点为界,DKK1高表达组(16/20)与低表达组(4/20)PFS之间差异明显(P<0.05)。相关性分析显示,DKK1和PFS显著相关(Pearson相关系数为-0.528,P=0.017)。结论LUAD伴LM患者CSF中DKK1表达及动态变化可能与LM的发生、发展及耐药密切相关。

Objective To analyze the correlation between DKK1 in the CSF and the morbidity,drug resistance and prognosis of LUAD-LM so as to seek a new biomarker for guiding accurate treatment.Methods 20 LUAD-LM patients who received regular intrathecal chemotherapy with pemetrexed were divided into the disease control(DC)group and the progressive disease(PD)group according to RANO criteria.CSF samples from all patients and additional 10 participants of nonmalignant brain diseases were obtained.The CSF of the DC group was divided into three groups:the DC-0C group(before treatment),the DC-2C group(two cycles after treatment)and the DC-4C group(four cycles after treatment).The levels of DKK1 expression in CSF were detected by ELISA.Besides,the correlation between DKK1 and the clinical features,efficacy and progression-free survival(PFS)of LUAD-LM was evaluated.Results The level of DKK1 was dramatically up-regulated in the LM group compared with the control group(P<0.05),and the difference was more pronounced in the PD subgroup(P<0.05).In the course of intrathecal chemotherapy,the expression of DKKl in the DC group showed a decreasing trend generally,and there was a statistical difference between the DC-0C group and the DC-4C group(P<0.05).The optimal diagnostic cut-off point of DKK1 was 139.36 pg/mL on the basis of ROC curve(sensitivity 70%,specificity 80%,AUC 0.745).Their PFS had a significant difference between the DC group and the PD group(P<0.01).The difference of PFS between patients with high-expressed DKK1(16/20)and patients with low-expressed DKK1(4/20)was statistically significant(P<0.05)with the cut-off at 139.36 pg/mL.Correlation analysis showed that DKK1was closely related to PFS(Pearson correlation coefficient was-0.528,P=0.017).Conclusion The expression and dynamic changes of DKK1 in CSF are closely related to the occurrence,development and drug resistance of LUAD-LM.